This royal decree develops Chapter VI of Title II of Law 29/2006 of July 29 on the guarantees and rational use of medicinal products and medical devices, which establishes the guarantees for the monitoring of the benefit-risk in medicinal products and therefore regulates the Spanish Pharmacovigilance and Pharmacovigilance System for medicinal products for human use. In addition, with this royal decree, the regulation so far in force in this field, collected in Royal Decree 711/2002 of 19 July 2002, which regulates the pharmacovigilance of medicinal products for human use, is updated and adapted to technical progress. the new developments introduced by Directive 2004 /27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001 /83/EC on the establishment of a code of conduct for the purposes of Directive 2004 /27/EC are hereby repealed and incorporated into national law. Community on medicinal products for human use. The new features introduced in Title IX "Pharmacovigilance" of Directive 2001 /83/EC of the European Parliament and of the Council of 6 November 2001 are a consequence of the changes resulting from the international harmonisation of the definitions, terminology and technological development, which forces the systems of pharmacovigilance in the European Union to adapt permanently to scientific and technical progress. Among these innovations introduced by the new European legislation and which makes this royal decree, it highlights the requirement of electronic notification of adverse reactions among the different agents (pharmaceutical industry, national agencies and European Medicines Agency), in order to enable the creation and maintenance of a European database of suspected adverse reactions, to be managed by the European Medicines Agency, ensuring its accessibility to the Member States. It also highlights the introduction of the concept of risk management, with the understanding of the planning of pharmacovigilance activities with the intention of anticipating the safety problems of medicinal products, as well as the introduction of measures to minimise the known risks of medicinal products and to enable their effective communication, with particular reference to the pharmacoepidemiology and, in particular, to post-authorisation studies which should contribute to identifying and characterising the risks of medicinal products and to assess the effectiveness of these minimisation measures risks. It is also important to amend the definitions of "risks associated with the use of medicinal products" and of "balance or benefit-risk balance", which are included in this provision. Finally, it should be noted that Directive 2004 /27/EC of the European Parliament and of the Council of 31 March 2004 incorporates a new Article 102a of Directive 2001 /83/EC of the European Parliament and of the Council of 6 November 2001 on the the permanent control of the authorities on the management of the funds for the activity of pharmacovigilance, the operation of the communication networks and the market, as a fundamental guarantee for the preservation of their independence, which has already been operating in Spain and must also be moved to the field of pharmacoepidemiology, so that, with the necessary independence, studies that are of particular interest to protect public health are carried out from the public sector. In view of this background, this royal decree establishes, first of all, the agents involved in the Spanish Pharmacovigilance System for medicinal products for human use, as well as the obligations of each of the agents involved. in this activity, the aim of which is to provide on a continuous basis the best possible information on the safety of medicinal products, to enable the adoption of appropriate measures and to ensure, in this way, that the medicinal products available in the market has a beneficial benefit-risk relationship for the population in the conditions of use authorised. For the exercise of pharmacovigilance for medicinal products for human use, the European Commission has drawn up and published the guidelines contained in Volume 9A of the Rules on medicinal products in the European Union which will be applicable, as well as their successive updates. Secondly, the administrative consequences for safety reasons may affect the conditions for authorization to place medicinal products for human use on the market and, finally, the post-authorisation studies are regulated. in order to ensure that the risk-benefit assessment of the authorised medicinal product is ongoing. In the preparation of this provision, the sectors affected and the autonomous communities have been consulted. This royal decree, which has the status of legislation on pharmaceutical products in accordance with the provisions of Article 149.1.16 of the Constitution, incorporates in the internal legal order paragraphs 1.i) and 72 to 76 of Article 1 of Directive 2004 /27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001 /83/EC on the Community code relating to medicinal products for human use. In its virtue, on the proposal of the Minister of Health and Consumer Affairs, with the prior approval of the Minister of Public Administrations, in agreement with the Council of State and after deliberation of the Council of Ministers at its meeting on October 11, 2007,

D I S P O N G O:

CHAPTER I

General provisions

Article 1. Scope of application.

The provisions of this royal decree apply to the pharmacovigilance of medicinal products for human use, as a public health activity that aims to identify, quantify, evaluate and prevent risks associated with the use of medicinal products once marketed.

Article 2. Definitions.

For the purposes of this royal decree, the following definitions shall apply: (a) Spanish Pharmacovigilance System for medicinal products for human use: Decentralised structure, coordinated by the Spanish Agency for Medicines and Health Products, which integrates the activities carried out by the Health Administrations continuous and continuous way to collect, develop and, where appropriate, process information useful for the supervision of medicinal products and, in particular, information on adverse reactions to medicinal products, as well as for the performance of studies are considered necessary to assess the safety of medicinal products.

b) Spontaneous Reporting Programme: Pharmacovigilance method based on the communication, collection and evaluation of reports of suspected adverse drug reactions. (c) Adverse reaction: Any response to a medicinal product which is harmful and unintended, and which occurs at doses normally applied in the human being for the prophylaxis, diagnosis or treatment of diseases, or for the restoration, correction or modification of physiological functions. This term also includes all harmful clinical consequences arising from the dependence, abuse and improper use of medications, including those caused by use outside of authorized conditions and those caused by errors of medication. d) Serious adverse reaction: Any adverse reaction that causes death, may endanger life, requires hospitalization of the patient or prolongation of the existing hospitalization, causes a significant disability or disability or persistent or constitute a birth defect or birth defect. For the purposes of their notification, serious suspected adverse reactions which are considered to be important from the medical point of view, even if they do not meet the above criteria, such as those at risk to the patient or require an intervention to prevent any of the previous outcomes. For the purposes of their notification, all suspicions of transmission of an infectious agent through a medicinal product shall be treated as serious. (e) Unexpected adverse reaction: Any adverse reaction whose nature, severity or consequences are not consistent with the information described in the technical information sheet. (f) Periodic Safety Report: Document prepared by the Marketing Authorisation Holder in accordance with the guidelines established in this regard in the European Union, the purpose of which is to update the safety information for the medicinal product which, among other elements, contains information on the suspected adverse reactions of which it has become aware in the reference period, as well as a scientific assessment of the benefit-risk balance of the medicinal product. (g) Post-authorisation study: Any clinical or epidemiological study carried out during the marketing of a medicinal product in accordance with the conditions authorised in its technical file, or under normal conditions of use, in which the medicinal product or Medicinal products of interest are the fundamental exposure factor investigated. This study may take the form of a clinical trial or an observational study. (h) Safety post-authorisation study: Pharmacoepidemiological study or clinical trial carried out in accordance with the provisions of the marketing authorisation and carried out for the purpose of identifying, characterizing or quantifying the risks associated with authorised medicinal products. (i) Abuse of a medicinal product: excessive and voluntary use, persistent or sporadic, which may be the cause of physical or psychological harmful effects. (j) Yellow card: form for the notification of suspected adverse reactions, distributed by the competent authorities in the field of pharmacovigilance of the autonomous communities to healthcare professionals. k) Good pharmacovigilance practices: Set of standards or recommendations to ensure:

1. The authenticity and quality of the data collected in pharmacovigilance, in order to assess at any time the risks associated with the use of the medicinal products;

2. The confidentiality of information regarding the identity of patients and healthcare professionals; 3. The use of homogeneous criteria in the management of pharmacovigilance information.

l) Risks associated with the use of the medicinal product: Any risk to the health of the patient or public health related to the quality, safety and efficacy of the medicinal product, as well as any risk of adverse effects. desired in the environment.

m) Balance or benefit-risk ratio of the medicinal product: Valuation of the favourable therapeutic effects of the medicinal product in relation to the risks associated with its use. (n) Risk Management Plan: A document in which the applicant or marketing authorisation holder specifies the significant risks of the medicinal product, identified or potential, and points out the relevant safety information available; establishes a plan for the implementation of the pharmacovigilance activities necessary to identify, characterise or quantify them; and incorporates, if necessary, a specific risk prevention or minimisation programme, including training and information activities for professionals and users in the the context of such a plan and the assessment of the effectiveness of the measures taken. n) Medication error: Failure by action or omission in the treatment process with medicinal products that causes or can cause damage to the patient. Medication errors that result in damage to the patient will be considered for the purpose of their notification as adverse reactions, except for those derived from the treatment failure.

Article 3. Sources of information in pharmacovigilance.

1. Information on the risks associated with the use of medicinal products may come from the following sources: (a) Spontaneous reporting of individual cases of suspected adverse reactions by healthcare professionals.

b) Post-authorization studies. (c) Databases of computerised health data. (d) Preclinical animal testing information. (e) Information on clinical trials of a medicinal product. (f) Information related to the manufacture, preservation, sale, distribution, dispensing, prescription and use of the medicinal products. (g) Scientific publications. (h) Other sources of information, such as those relating to the misuse and abuse of medicinal products, or those relating to medication errors, which may provide relevant data for the assessment of the benefits and risks of medicinal products. (i) Other health authorities and international health bodies.

2. The Spanish Agency for Medicinal Products and Sanitary Products shall establish the necessary conventions with the competent bodies of the autonomous communities for the shared use of the sources of information that are identified in the paragraphs (c), (f) and (h) of the previous paragraph.

3. In order to facilitate the exchange of information on individual cases of suspected adverse reactions, the guidelines developed and published by the European Commission in Volume 9A of the Rules on Medicinal Products in the Union shall apply. European, relating to the collection, verification and reporting of adverse reactions, including technical requirements for the electronic exchange of pharmacovigilance information, in accordance with the formats agreed internationally and on internationally accepted medical terminology.

CHAPTER II

The Spanish Pharmacovigilance System for Medicinal Products for Human Use

Article 4. Agents of the Spanish Pharmacovigilance System for medicinal products for human use.

1. The Spanish Pharmacovigilance System for medicinal products for human use consists of: (a) the Spanish Agency for Medicines and Health Products, which acts as the coordinating centre.

(b) The pharmacovigilance bodies responsible for the pharmacovigilance of the autonomous communities and the pharmacovigilance units or centres of pharmacovigilance to which they are attached. c) Healthcare professionals.

2. The Technical Committee of the Spanish Pharmacovigilance System for medicinal products for human use, as an organ of coordination consisting of the Spanish Agency for Medicinal Products and Sanitary Products and the competent authorities in the field of pharmacovigilance the autonomous communities, or units in which they delegate, shall unify the criteria for the functioning of the spontaneous reporting programme, assess the alert signals generated by the Spanish Pharmacovigilance System for medicinal products for human use and discuss the methodological and practical aspects of how many studies are proposed perform in your breast.

Article 5. Duties of the Spanish Agency for Medicinal Products and Sanitary Products in the field of pharmacovigilance for medicinal products for human use.

1. They are the functions of the Spanish Agency for Medicines and Health Products: a) Coordinate and evaluate the Spanish Pharmacovigilance System for medicinal products for human use, as well as carry out the secretarial tasks of its Technical Committee, according to the 'Good Pharmacovigilance Practice of the Spanish Pharmacovigilance System for medicinal products for human use' developed by the Technical Committee and published by the Ministry of Health and Consumer Affairs. It is also up to the planning and development of this system in relation to the autonomous communities.

In the exercise of its coordination powers, the Spanish Agency for Medicines and Health Products will supervise the permanence and continuity of the spontaneous notification program in the respective autonomous communities, and present an annual report on the activities of the Spanish Pharmacovigilance System for medicinal products for human use to the Committee for the Safety of Medicinal Products for Human Use. (b) Establish, in collaboration with the Autonomous Communities, a data processing network that enables the competent authorities in the field of pharmacovigilance of the Autonomous Communities, or units in which they delegate, to be accessible in a manner telematics all information collected by the Spanish Pharmacovigilance System for medicinal products for human use. c) Manage the database of the Spanish Pharmacovigilance System for medicinal products for human use, ensuring at all times their availability and updating, monitoring their safety and ensuring the confidentiality of the data and their integrity during data transfer processes. The Ministry of Health and Consumer Affairs will establish the terms in which this information will be made available to the public. (d) Act as a reference centre for the Spanish Pharmacovigilance System for medicinal products for human use with the holders of marketing authorisations for medicinal products and with international organisations, without prejudice to the powers of the the pharmacovigilance issues of the autonomous communities. (e) to make available to the marketing authorisation holder immediately, and in any event within 15 calendar days of receipt, notifications of suspected serious adverse reactions which have occurred; produced in Spain and in which they are involved as suspected medicinal products for which they are the holders. Any other pharmacovigilance information not referred to in the preceding subparagraph shall be expressly requested by the person concerned in accordance with the procedure laid down for that purpose. (f) to transmit to the European Medicines Agency and to the other Member States immediately, and in any event within 15 calendar days of receipt, the notifications of suspected serious adverse reactions which have been have been produced in Spain. This communication will be carried out through the data processing network which the European Medicines Agency will establish in collaboration with the Member States and the European Commission. g) Promote the creation of computerized health data bases that serve as a source of information for the conduct of pharmacoepidemiological studies with the participation of the health authorities of the autonomous communities and the health professionals. (h) Promote and carry out the pharmacoepidemiology studies necessary to assess the safety of authorised medicinal products. i) Evaluate the information received from the Spanish Pharmacovigilance System, as well as other sources of information. In particular, the Agency shall assess the information from the periodic safety reports, the risk management plans and the post-authorisation studies which have implications for the safety of medicinal products. (j) Establish appropriate measures for the management of the identified risks, including the necessary training and information, with the ultimate aim of minimising or preventing them. (k) Ensure public access to information submitted by marketing authorisation holders or by any other entity or person deemed to be particularly relevant for the protection of public health. (l) Establish, in conjunction with the autonomous communities, the relevant inspection procedures to ensure that the obligations of the marketing authorisation holders referred to in Article 8 are complied with. (m) Any other function which may be necessary in the field of pharmacovigilance and which must be carried out by the Spanish Agency for Medicinal Products and Sanitary Products.

2. The Spanish Agency for Medicinal Products and Sanitary Products shall ensure, in its field of competence, the means necessary to carry out pharmacovigilance and risk management, as well as the independent conduct of studies which are precise to assess the safety of the medicinal products.

Article 6. Participation of the Autonomous Communities in the Spanish Pharmacovigilance System for medicinal products for human use.

1. The Spontaneous Reporting Programmes that the Autonomous Communities will develop on a permanent and ongoing basis will be in line with the good pharmacovigilance practices of the Spanish Pharmacovigilance System for medicinal products for human use which publish the Ministry of Health and Consumer Affairs.

2. The Autonomous Communities shall record in the database of the Spanish Pharmacovigilance System the notifications of suspected serious adverse reactions within the maximum period of 10 calendar days from the receipt of the information. The Spanish Agency for Medicinal Products and Sanitary Products may require the health authorities of the autonomous communities to provide information to assess the safety of medicinal products. 3. The Autonomous Communities shall cooperate with the Spanish Agency for Medicinal Products and Sanitary Products for the implementation and development of programmes and studies on the evaluation and management of the risks of medicinal products, in accordance with the agreements adopted by the Committee on the Safety of Medicinal Products for Human Use and by the Spanish Technical Committee for Pharmacovigilance of Medicinal Products for Human Use. 4. The Autonomous Communities and the Spanish Agency for Medicines and Health Products shall cooperate in the dissemination of knowledge on the safety of medicinal products in the field of care.

Article 7. Obligations of healthcare professionals.

Doctors, pharmacists, dentists, nurses and other healthcare professionals have an obligation to: (a) Notify suspected adverse reactions of authorised medicinal products, including those of those who have used under conditions other than those authorised and those for medicinal products not marketed in Spain but which have been authorised to be imported in accordance with Article 24 (4) of Law 29/2006 of 26 July. These notifications shall be sent as soon as possible to the competent authority in the field of pharmacovigilance of the autonomous community corresponding to their care, by means of the form for the collection of suspected adverse reactions. ("yellow card").

Priority shall be given to the notification of serious or unexpected adverse reactions of any medicinal product and those related to new medicinal products identified by the yellow triangle described in Article 8.2. Where the suspicion of adverse reaction is the result of a medication error, as defined in Article 2 (n), the notification may be made in accordance with special procedures to be agreed by the Technical Committee of the The Spanish Pharmacovigilance System and to be collected in the document of "Good Pharmacovigilance Practice of the Spanish Pharmacovigilance System for Medicinal Products for Human Use". (b) Keep clinical documentation of suspected adverse drug reactions in order to complete or follow up, if necessary. c) Cooperate with the Spanish Pharmacovigilance System for medicinal products for human use, providing the necessary information to them to identify, characterize or quantify adverse reactions or to extend or complete the information on suspected adverse reactions reported. (d) to be kept informed of the safety data relating to medicinal products which are normally prescribed, dispensed or administered, and to carry out the risk prevention measures laid down in the technical fiche of the medicinal product, including training and information measures for users. (e) Collaborate with the risk management plans, in particular for medicinal products that are qualified as special medical control. (f) Collaborate with the pharmacovigilance officers of the marketing authorisation holders in case of a suspected adverse reaction to one of their medicinal products, providing the information necessary for their subsequent notification the Spanish Pharmacovigilance System by the holder. (g) to collaborate, as experts, with the Spanish Agency for Medicines and Health Products and the competent bodies of the Autonomous Communities, in the evaluation of the safety problems of medicinal products for human use.

CHAPTER III

From marketing authorization holders

Article 8. Obligations of the marketing authorisation holder.

1. The marketing authorisation holder, in accordance with the 'Good Pharmacovigilance Practice for medicinal products for human use for the pharmaceutical industry', published by the Ministry of Health and Consumer Affairs, shall: a detailed record of all suspected adverse reactions occurring in Spain, in the European Union or in a third country. Except in exceptional circumstances, such as technical impossibility, the suspicion of individual cases of adverse reactions meeting the criteria set out in paragraphs (b) to (g) shall be communicated by electronic means in accordance with the guidelines set out in Volume 9A of the Rules on Medicinal Products in the European Union. According to these guidelines, marketing authorisation holders will use the internationally accepted medical terminology.

(b) Register and report suspected serious adverse reactions in Spain to the pharmacovigilance body of the Autonomous Community where the health professional who has reported the activity is active. of the case. Such notification should be made immediately, and in any case within 15 calendar days of receipt of the information. Suspected serious adverse reactions associated with authorised medicinal products, including those of those that have been used under conditions other than those authorised, and those associated with non-marketed medicinal products should be reported. in Spain but that their importation has been authorised in accordance with Article 24 (4) of Law 29/2006 of 26 July. It shall also notify any other suspected serious adverse reaction occurring in Spain and of which it can reasonably be expected to have knowledge. If the communication is made on paper, any of the official languages of the relevant autonomous community should be used. Where the notification is made in a European standard electronic format, it shall be made directly to the data processing network of the Spanish Pharmacovigilance System for medicinal products for human use, as referred to in Article 5.1.b), European Union standards, including case narration, which must be made in the official language of the State and include a translation into the English language. The Spanish Agency for Medicines and Health Products will publish the guidelines to be followed in relation to this electronic notification. Where the suspicion of adverse reaction is the result of a medication error, as defined in Article 2 (n), the notification may be made in accordance with special procedures to be agreed by the Technical Committee of the The Spanish Pharmacovigilance System and to be collected in the document of "Good Pharmacovigilance Practices for medicinal products for the pharmaceutical industry". (c) Ensure that all suspicions of serious and at the same time unexpected adverse reactions of medicinal products authorised in Spain which occur outside the European Economic Area, of which he has knowledge through a professional of the health services, are communicated to the Spanish Agency for Medicines and Health Products immediately and in any case within 15 calendar days of receipt of the information. Where the notifications referred to in this paragraph are made in the European standard electronic format, Spain shall be deemed to have been notified of any suspected adverse reaction sent to the database of the European Medicines Agency, the specific notification to Spain is not necessary. (d) to monitor the world scientific literature, in order to identify the published cases of adverse reactions where there is a reasonable suspicion that the causative is an active substance in a medicinal product for which marketing authorisation in Spain shall be the holder. These cases shall be reported in accordance with the criteria set out in paragraphs (b) and (c). e) Ensure that the suspected serious adverse reactions occurring during the course of a post-authorisation study, and of which they may be be reasonably expected to be aware, be communicated using the criteria specified in paragraphs (b) and (c) in accordance with the criteria set out in the guidelines set out in Volume 9A of the Rules on medicinal products in the European Union. (f) In the case of advanced therapy medicinal products, the communication of suspected adverse reactions shall be carried out in accordance with the criteria specified in paragraphs (b) and (c). However, where suspected adverse reaction involves the transmission of a disease or problem, either by contamination during the process, or because it is already contained in the tissue or cell group, the holder shall endeavour to carry out the (a) notification within a period of not more than 48 hours, stating in that communication the single European code of the donation established by Royal Decree 1301/2006 of 10 November establishing the quality and safety standards for the donation, procurement, evaluation, processing, preservation, storage and the distribution of human tissues and cells and the standards of coordination and functioning for human use are approved. (g) to ensure, in the case of medicinal products whose reference Member State is Spain, that they have been authorised by the mutual recognition procedure, or decentralised, or have been the subject of a Community decision, that all suspicions of serious adverse reactions occurring outside Spain but in the territory of the European Union are reported in the format and intervals indicated by the Spanish Agency for Medicines and Health Products for analysis and monitoring of these adverse reactions for the whole of the European Union. Where the notifications referred to in this paragraph are made in the European standard electronic format, Spain shall be deemed to have been notified of any adverse reactions sent to the database of the European Medicines Agency or to the the competent authority of the Member State concerned if it occurs within the European Union, the specific notification to Spain is not necessary. (h) Submit the records of all suspected adverse reactions to the Spanish Agency for Medicinal Products and Sanitary Products in a periodic safety report, in accordance with the guidelines set out in Volume 9A of the Rules on medicines in the European Union. Such presentation shall be made immediately at the request of the Spanish Agency for Medicinal Products and Sanitary Products, and on a regular basis in accordance with the time limits laid down in this paragraph, provided that no other requirements as a condition for granting marketing authorisation for the medicinal product. The frequency of submission of the reports shall be half-yearly from the authorisation and until the marketing year. Once they are placed on the market, they shall be submitted semi-annually for the first two years after first placing on the market in any country of the European Union and annually for the following two years. From that point on, the periodic safety report shall be submitted at intervals of three years. This frequency shall apply to all medicinal products irrespective of their date of authorisation. The holder may request the modification of the periods referred to in the preceding subparagraph, together with the application for authorisation, or after the application has been granted in accordance with the procedure laid down in the rules governing the assessment, registration, authorisation and conditions for the supply of medicinal products for human use manufactured industrially. The circumstances in which the periodicity of submission of periodic safety reports is required to be restarted are described in Volume 9A. In such circumstances, if the holder considers that the start of the periodicity is not required, he must apply for an exemption at the time of the authorisation, or once the authorisation has been granted in accordance with the procedure laid down in the legislation for which he is regulates the assessment, authorisation, registration and dispensing of medicinal products for human use manufactured industrially. In any case, the start of the periodicity shall be compulsory when an indication is added for paediatric use of a medicinal product which does not have it. On the occasion of the renewal of the authorisation, the holder of the authorisation shall follow the instructions of Volume 9A with regard to the submission of the relevant periodic safety report. i) Perform post-authorisation studies to generate additional information on the characteristics of the use of the medicinal products, confirm, quantify or characterize potential risks, or to provide new scientific information on the relationship benefit-risk of authorised medicinal products in Spain. (j) Carry out a continuous assessment of the benefit-risk ratio of the medicinal products authorised in Spain and immediately communicate to the Spanish Agency for Medicinal Products and Health Products any new information which may influence the overall assessment of the benefit-risk relationship or may require modification of the technical information sheet, package leaflet or both. You must also immediately notify the Spanish Medicines and Health Products Agency of any restrictions, suspension or prohibition imposed by the competent authorities of any country. k) Provide a benefit-risk report when the Spanish Medicines and Healthcare Products Agency requests it. (l) Carry out the pharmacovigilance and risk management plans for each medicinal product to be established, including studies which the competent authorities consider necessary to assess the safety of the medicinal product, or to evaluate the effectiveness of risk minimisation measures. (m) Not to communicate to the public data on pharmacovigilance issues relating to its authorised medicinal product without prior notification, at least 24 hours, to the Spanish Agency for Medicinal Products and Sanitary Products. The marketing authorisation holder shall ensure that the information is presented in an objective manner and is not misleading, and without ignoring relevant safety information. The lack of communication to the Agency or the dissemination of information without respecting the terms set out in this paragraph shall be considered as a breach of the pharmacovigilance duty provided for in Article 101.2.b.14 of Law 29/2006 of 26 July. The Agency shall take the necessary measures to ensure compliance with this obligation. (n) Carry out in Spain the regulatory measures taken for safety reasons for the medicinal products for which it is a holder, as well as all measures and studies included in the risk management plan and which are to be carried out in Spain. To establish appropriate procedures for medical visitors to comply with the duty to notify them of all information concerning the use of medicinal products for which they are intended to be promoted, in particular with regard to reactions adverse events that the people visited communicate to them.

2. For medicinal products containing active substances not previously authorised in Spain, the holder shall be obliged to include in all catalogues, promotional materials and any other material for dissemination to professionals. the pictogram set out in the Annex, for the first five years after authorisation. For medicinal products with active substances already authorised, the pictogram shall appear until the first five years after the authorisation of the first medicinal product containing them are fulfilled.

When relevant modifications are introduced that may affect the safety profile of the medicinal product, such as new routes of administration, new combinations, new indications for different populations than usual, and Any other, by a reasoned decision of the Spanish Agency for Medicinal Products and Sanitary Products, may establish a longer period. 3. This Article shall not apply to holders of authorisation for homeopathic medicinal products registered under the special simplified procedure, except for the obligations laid down in paragraph 1 (j) and (k).

Article 9. Person responsible for pharmacovigilance.

1. The holder of the authorisation to place a medicinal product for human use on the market must have a suitably qualified person responsible for pharmacovigilance in Spain, permanently and continuously. The marketing authorisation holder shall communicate to the Spanish Agency for Medicinal Products and Sanitary Products, as well as to the pharmacovigilance bodies of the autonomous community in which he is based, the name of the responsible. The Spanish Agency for Medicines and Health Products will keep a register of these responsible.

2. The person responsible for pharmacovigilance shall have the following functions:

a) Create and maintain a system to collect, treat and evaluate information on all suspected adverse reactions reported to the company's staff and medical visitors, in order to make it accessible at least in one place in the European Union.

b) Prepare and submit to the Spanish Agency for Medicinal Products and Health Products the periodic safety reports referred to in Article 8.1.h. c) Ensure that a rapid and comprehensive response to any request for additional information from the Spanish Agency for Medicines and Health Products is required to be able to assess the benefits and risks of a medicinal product, including information on the volume of sales or prescriptions of the medicinal product concerned. (d) to provide the Spanish Agency for Medicinal Products and Health Products with any other information of interest for the assessment of the benefits and risks associated with a medicinal product, including information on post-authorisation safety studies. (e) Ensuring the necessary mechanisms to carry out in Spain regulatory measures taken for safety reasons for medicinal products for which pharmacovigilance is responsible, as well as all measures and studies included in the plan for risk management and to be carried out in Spain. f) Act as a point of contact for pharmacovigilance inspections carried out in Spain.

3. The preceding paragraphs shall not apply to holders of authorisation for homeopathic medicinal products registered under the special simplified procedure.

Article 10. Information provided by the marketing authorisation holder for safety reasons.

1. The marketing authorisation holder is obliged to disseminate the updated technical information sheet of the medicinal product to healthcare professionals, together with the information provided for in Article 15.2 of Law 29/2006 of 26 July. In addition, the technical information sheet authorised by the Spanish Agency for Medicinal Products and Sanitary Products must be made available to the health authorities.

2. Where, at the discretion of the marketing authorisation holder or the Spanish Agency for Medicinal Products and Sanitary Products, the first report to healthcare professionals on new safety data is deemed necessary. the medicinal product or the prevention of risks, and it is decided to send individual letters to each healthcare professional concerned, it must be agreed in advance with the Spanish Agency for Medicines and Health Products the text, if any complementary, as well as the shipping schedule and the type of healthcare professional to which you are heading. In all cases it must be incorporated into it on a flag indicating the nature of the information contained therein.

CHAPTER IV

From administrative intervention

Article 11. Advisory body and participation of experts in the evaluation of the safety of medicinal products.

1. The Spanish Agency for Medicinal Products and Sanitary Products will have the Committee for the Safety of Medicinal Products for Human Use, a collegiate body provided for in Royal Decree 520/1999 of 26 March, approving the Statute of the Spanish Agency. for medicinal products and health products, for advice on pharmacovigilance and the composition of which shall be made public.

2. The Spanish Agency for Medicines and Health Products will be able to request the advice of drug safety experts and in other medical and scientific areas, among which will be the technicians of the Spanish System of Pharmacovigilance of medicinal products for human use designated by the competent bodies in each Autonomous Community. Such experts may assess specific safety concerns, post-authorisation studies, periodic safety reports, risk management plans and requests for amendments to the technical information sheet.

Article 12. Amendment of the authorisation for reasons of pharmacovigilance.

1. In accordance with Article 17.9 of Law 29/2006 of 26 July, where the holder of a marketing authorisation for a medicinal product is aware of new relevant information affecting the safety of that medicinal product, including his knowledge by means of circular or individual notification of the Spanish Agency for Medicinal Products and Health Products, shall update without delay the dossier of authorisation and registration, by means of the procedures for the modification of the conditions for the authorisation of medicinal products for human use, their failure to comply with suspension or revocation of the authorisation. This amendment shall be subject to the payment of the corresponding fee.

2. Where the evaluation of pharmacovigilance data is based on reasons of public interest, protection of the health or safety of persons, the Spanish Agency for Medicinal Products and Health Products may restrict the conditions of authorisation. of a medicinal product, and to establish any of the reserves or restrictions of the scope of use listed below, as defined in the rules for the authorisation, registration and conditions of supply of medicinal products for use industrially manufactured human:

a) Medicament for hospital use (H).

b) Medical diagnosis or prescription by certain medical specialists (DH). c) Special medical control medicine (ECM).

Article 13. Suspension or revocation of the authorisation for reasons of pharmacovigilance.

1. The Spanish Agency for Medicinal Products and Sanitary Products, in accordance with the assessment of pharmacovigilance data, may temporarily suspend or revoke the authorisation of a medicinal product when: (a) under the conditions of Common use has an unfavourable benefit-risk ratio.

b) For any other cause, pose a foreseeable risk to the health or safety of people. (c) the pharmacovigilance rules are not complied with, in accordance with the provisions of Article 22.1 (d) of Law 29/2006 of 26 July. (d) The European Medicines Agency would have agreed.

2. For reasons of public health, and pending the termination of the suspension or revocation procedure, the precautionary suspension of marketing may be imposed by means of a reasoned decision. In such cases, the person concerned must withdraw the product from the market, without prejudice to a performance by the Spanish Agency for Medicines and Health Products where the urgency of the case so requires. The costs incurred by such measures shall be borne by the person concerned, without, in any event, a penalty.

Article 14. Assessment and procedure in cases where a suspension or revocation of the marketing authorisation or the relevant modification of the authorised conditions of use may result.

1. Where the Spanish Medicines and Health Products Agency considers that there are any circumstances under Articles 12.2 and 13 for the purposes of pharmacovigilance, as a reason for the relevant modification of the conditions of use The following actions shall be followed: authorised or revoked or suspended, respectively: (a) The Agency shall ask the marketing authorisation holder for a report assessing the safety concern identified and, where appropriate, the risk-benefit ratio of the medicinal product to the conditions of use authorised in Spain, including a proposal for risk mitigation measures. This report shall be in accordance with the structure and issues specified in the application of the Spanish Agency for Medicinal Products and Sanitary Products. The report shall be sent within a maximum of 60 days from the receipt of the request, unless the urgency of the problem is established by the Agency for a shorter period, or in exceptional cases and at the request of the holder, the Agency a longer term.

(b) In the light of the report, the Spanish Agency for Medicines and Health Products will draw up an assessment report on the safety problem. (c) If the above report shows the need for a measure of suspension or revocation of the authorisation, or the relevant modification of the conditions of use for safety reasons, the initiation of the procedure shall be agreed upon ex officio corresponding. In all cases where a suspension or revocation of the authorisation may be derived, the Committee on the Safety of Medicinal Products for Human Use shall deliver a mandatory but non-binding opinion. In specific cases where the interests of the European Union, the Spanish Agency for Medicinal Products and Sanitary Products are at stake, or the marketing authorisation holder may refer the matter to the Committee for Medicinal Products for Use Human rights of the European Medicines Agency, in order for a Community decision to be taken. (d) After hearing the person concerned, a decision shall be taken to indicate the resources and shall be notified to the person concerned. This procedure shall be resolved and notified at the latest within six months, without prejudice to the interruption of the deadline for the release of the report of the Committee on the Safety of Medicinal Products for Human Use and the Committee for Medicinal Products for Human Use. of the European Medicines Agency, in cases where the interests of the European Union are at stake, in accordance with Article 83.3 of Law No 30/1992 of 26 November 1992 on the legal system of public administrations and the procedure Joint Administrative.

2. In the case of the procedure for amending the authorisation, the decision shall indicate the changes to be made to the technical information sheet, package leaflet, labelling and scope of use of the medicinal product, as well as other measures aimed at reducing the risk and inform healthcare professionals and users.

In accordance with these indications, the marketing authorisation holder shall request the appropriate modification of the conditions for the authorisation of the medicinal product in accordance with the procedures laid down in the regulations, for the authorization, registration and conditions of supply of the medicinal products for human use manufactured industrially. 3. The procedure laid down in this Article shall not apply to medicinal products authorised by the centralised procedure laid down in Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 establishing Community procedures for the authorisation and control of medicinal products for human and veterinary use and establishing the European Medicines Agency, which shall be governed by its specific rules.

Article 15. Urgent amendments for reasons of security and applicable procedure.

1. Where new information is known to indicate an important risk to public health associated with the use of the medicinal product or has a relevant impact on the safety of the medicinal product, the Spanish Agency for Medicinal Products and Products Health care may agree to the temporary and urgent change in the information of the medicinal product which will affect in particular one of the following sections of the technical fiche: indications, posology, contraindications, warnings and precautions Special employment.

2. Where the holder considers it necessary to modify the conditions for the authorisation of a medicinal product for safety reasons, he shall request that amendment to the Spanish Agency for Medicinal Products and Health Products, accompanying the next documentation:

a) Report on the identified risks that make the modification necessary.

b) Proposed amendment of the Summary of Product Characteristics and Package Leaflet. (c) Proposal for information to health professionals and, where appropriate, to users. (d) Proposal for further action, as well as any other information deemed necessary for the effective implementation of the amendment.

If the Spanish Agency for Medicines and Health Products does not raise any objection within the next business day to the receipt of the information, urgent modifications for safety reasons will be considered accepted. on a provisional basis. The marketing authorisation holder shall request the modification of the technical information sheet within a period not exceeding the following 15 calendar days from the date of acceptance. The Spanish Agency for Medicines and Health Products will establish the specific procedures to be followed.

3. Where the urgent amendment for safety reasons is imposed by the Spanish Agency for Medicinal Products and Sanitary Products, the holder shall be obliged to submit a request for amendment in the terms laid down by the Agency. immediate and within a period not exceeding 15 calendar days following receipt of the notification from the Agency. 4. In the cases referred to in paragraphs 2 and 3, the time limit and the terms of the information addressed to healthcare professionals, as well as the effective implementation of the amendment by the holder, including changes in the material The Agency will be agreed with the Spanish Agency for Medicines and Health Products. 5. In the case of products authorised under the mutual or decentralised recognition procedure, account shall be taken of the harmonisation mechanisms to be established for this purpose in the European Union through the relevant guidelines. For products authorised in accordance with the centralised procedure, the provisions specified in Commission Regulation (EC) No 1084/2003 of 3 June 2003 concerning the examination of amendments to the terms of the procedure shall be followed. authorisations for the placing on the market of medicinal products for human use and veterinary medicinal products granted by the competent authority of a Member State, and the guidelines implementing it.

Article 16. Communications and precautionary measures.

1. If the Spanish Agency for Medicinal Products and Health Products, in the light of the pharmacovigilance data, considers that a marketing authorisation should be subject to suspension, revocation or amendment involving a restriction relevant to the use of the medicinal product, it shall immediately inform the autonomous communities, the European Medicines Agency, the other Member States and the marketing authorisation holder.

2. In cases of urgency, in order to protect public health, the Spanish Agency for Medicinal Products and Sanitary Products may suspend the authorization to place a medicinal product on the market by the first working day following the following: the health authorities of the autonomous communities, the European Commission, the European Medicines Agency, the other Member States and the marketing authorisation holder. 3. The resolutions of suspension, revocation and relevant modification of the authorization, in so far as they may affect the public health of third countries, shall be brought to the attention of the World Health Organization.

Article 17. Amendment, suspension and revocation of the authorisation of medicinal products authorised by mutual and decentralised recognition procedures.

1. Without prejudice to Article 14, where the Spanish Agency for Medicinal Products and Health Products, in accordance with the assessment of pharmacovigilance data, considers it necessary for reasons of public health to amend it, suspension or revocation of the marketing authorisation for medicinal products authorised by mutual or decentralised recognition procedures, shall refer the matter to the Committee for Medicinal Products for Human Use of the European Agency for Medicinal products for the adoption of a Community decision.

2. Notified of the Community decision, without further processing the hearing of the person concerned, the Spanish Agency for Medicinal Products and Health Products shall adopt and notify the appropriate resolution, with an indication of the resources obtained, within 30 days. days from the notification of the Community decision. 3. Where a precautionary suspension of the medicinal product is justified, the provisions of Article 16.2 shall apply and the reasons for such suspension shall be reported, not later than the working day following that of the adoption of the measure, the health authorities of the autonomous communities, the European Commission, the European Medicines Agency, the other Member States and the marketing authorisation holder.

Article 18. Communication to the autonomous communities, health professionals and citizens.

1. The Spanish Agency for Medicines and Health Products will inform the autonomous communities and other responsible bodies about the adoption of the measures provided for in this chapter that are relevant to public health.

2. The Spanish Agency for Medicines and Health Products and the Autonomous Communities will make it possible to reach health professionals and citizens, in an appropriate manner, information on the risks of the drugs.

CHAPTER V

From post-authorization studies

Article 19. Applicable regime.

1. Post-authorisation studies shall be intended to supplement the information obtained during the clinical development of medicinal products prior to their authorisation. The planning, implementation or funding of post-authorisation studies is prohibited in order to promote the prescription of medicinal products.

2. The health authorities shall establish by common agreement the conditions under which the post-authorisation studies of an observational type are carried out in order to promote those which may contribute to the knowledge of the medicinal product or to improve clinical practice. The Spanish Agency for Medicines and Health Products will coordinate the actions to be carried out in this field and establish a Committee for the Coordination of Post-authorisation Studies with the participation of representatives of all the communities. and the Spanish Agency for Medicines and Health Products, which will discuss the guidelines of the common procedures that each community will implement in its field of competence. The functioning of this Committee shall be governed by the rules laid down in Law No 30/1992 of 26 November 1992 on the Legal Regime of Public Administrations and the Common Administrative Procedure for the collective bodies. 3. The Spanish Agency for Medicinal Products and Sanitary Products shall keep a record of the proposals for the post-authorization study of the observational type, to which the competent bodies of the autonomous communities will have access, and shall inform each promoter on the procedures to be followed in each case. To this end, the study promoter should send the study protocol to the Spanish Agency for Medicines and Health Products. 4. When the post-authorisation study, in accordance with the provisions of Article 58 of Law 29/2006 of 26 July, is of a clinical trial rather than an observational study, it shall not be governed by the provisions of this Chapter, but shall Royal Decree 223/2004 of 6 February, which regulates clinical trials with medicinal products for human use, will be implemented. 5. When carrying out a post-authorisation study of an observational type is a condition established at the time of the authorisation of a medicinal product, or it constitutes a requirement of the competent authority to clarify matters relating to the medicinal product concerned. the safety of the medicinal product, or part of the risk management plan to be carried out by the holder, shall require only the authorisation of the Spanish Agency for Medicinal Products and Health Products, in accordance with the procedures to be established to the effect. The Spanish Agency for Medicinal Products and Health Products shall inform the autonomous communities where they are to be carried out and shall include them in the register referred to in paragraph 3. 6. In the case of studies promoted by health administrations or financed from public funds, simplified procedures shall be established in order to facilitate their implementation and to be agreed in the Committee for the Coordination of Studies. Post-authorisation referred to in paragraph 2. 7. The sponsor of the study shall communicate to the Autonomous Communities where the study and the Spanish Agency for Medicines and Health Products are to be carried out, the date of the effective start of the study, and shall forward, where appropriate, the annual and final follow-ups, as well as the relevant protocol amendments. 8. In any case, the sponsor of a post-authorisation safety study shall take into account the guidelines set out in Volume 9A of the Rules on Medicinal Products in the European Union.

Single additional disposition. Cities with Autonomy Statute.

The references to the competent authorities in the field of pharmacovigilance of the autonomous communities will also be understood to be carried out in the cities with Autonomy Statute, with the scope provided for in their respective Statutes of Autonomy and real decrees for the transfer of powers.

Single repeal provision. Regulatory repeal.

The Royal Decree 711/2002 of 19 July 2002, which regulates the pharmacovigilance of medicinal products for human use, is hereby repealed.

Final disposition first. Character of legislation.

This royal decree is dictated by the development of Law 29/2006, of July 26, of guarantees and rational use of medicines and medical devices, and it has the character of legislation of pharmaceutical products for the intended effects in Article 149.1.16. of the Constitution.

Final disposition second. Faculty of development.

The Minister of Health and Consumer Affairs is empowered to make the necessary provisions for the correct application and development of this royal decree.

Final disposition third. Incorporation of European Union law.

By this royal decree, paragraphs 1.i) and 72 to 76 of Article 1 of Directive 2004 /27/EC of the European Parliament and of the Council of 31 March 2004 amending the Directive are incorporated into national law. 2001 /83/EC, establishing a Community code on medicinal products for human use.

Final disposition fourth. Entry into force.

This royal decree will enter into force on the day following its publication in the "Official State Gazette".

Given in Madrid, on October 11, 2007.

JOHN CARLOS R.

The Minister of Health and Consumer, BERNAT SORIA ESCOMS

ANNEX

Pictogram that identifies drugs with new active substances

The pictogram will be made up of an equilateral triangle, with the apex upwards, of black border and yellow background.

This pictogram will appear in visible place, to the left of the name of the medication, at least in the header of the information that is supplied, and it will be of a size similar to the letter of the name and at least 0.5 cm aside.